Process useful for preparing 7,8-acetamido, hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines

ABSTRACT

A chemical process is described for preparing 7,8-acetamido, hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines which involves reacting a 7,8-quinone derivative of a 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine with a benzyl or benzhydrylamine followed by hydrolysis of the resulting imine and reaction with acetic anhydride or acetyl chloride.

This is a division of Ser. No. 176,178 filed Aug. 7, 1980, now U.S. Pat.No. 4,327,023, which is a division of Ser. No. 117,181 filed Jan. 31,1980, now U.S. Pat. No. 4,284,556.

This invention relates to a new series of1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines whose structures arecharacterized by having 7,8-amino, hydroxy substituents. These compoundshave pharmacodynamic, activity indicating utility as central nervoussystem sedatives, diuretics, antidepressants, antihypertensive agents,and especially as dopaminergic agents. As indicative of dopaminergicactivity, pharmacological tests are used as described hereafter whichdemonstrate activity at central dopamine receptor sites indicatingutility as anti-parkinsonism agents or at peripheral dopamine receptorsites indicating renal dilation with resulting antihypertensiveactivity. Activity on the central nervous system is more pronounced withthe compounds of this invention. A further important utility for thesecompounds is their use as chemical intermediates for preparing otherpharmacodynamically active compounds as described in more detailhereafter.

PRIOR ART STATEMENT

There are in the art a number of general descriptions of the class of1-aryl-2,3,4,5-tetrahydro-1H-3-benzazepines having one or moresubstituents on the benz-ring of the nucleus such as in U.S. Pat. No.3,496,166 and 3,609,138. These patents however disclose generically onlythe possibility of having a dimethylamino or diethylamino substituent atan unspecified position on the benzo-fused ring of the nucleus with orwithout a large number of other substituents. None of the chemicalmethods described in the art can be used to prepare1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine compounds whose structureshave a primary amino group substituted in the benz-ring of the3-benzazepine nucleus. Also none of the examples in the art referencesdescribe specifically any 7 or 8-amino substituted1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines.

U.S. Pat. No. 4,165,372 in Example 8 discloses6-amino-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinedihydrobromide. The chemical methods of this patent cannot be used toprepare compounds whose structures have a primary amino substituent at aring position other than 6.

DESCRIPTION OF THE IVENTION

The compounds of this invention are represented by the followingstructural formula: ##STR1## in which: R is hydrogen, halo such asfluoro, iodo, chloro or bromo or lower alkyl of 1-3 carbons such asmethyl, ethyl or propyl;

R₁ and R₂ are hydroxy, amino, acetamido or methylsulfonamido providedthat one of R₁ and R₂ is always hydroxy and that R₁ and R₂ are not bothhydroxy;

R₃ is hydrogen, halo such as chloro, fluoro or bromo, methyl, methoxy,methylthio or hydroxy, and

R₄ is hydrogen, allyl or methyl.

A subgeneric group of compounds of this invention are those of Formula Iin which R₁ is amino, acetamido or methylsulfonamido and R₂ is hydroxy.The compounds of Formula I in which structures (1) R₁ is amino and R₂ ishydroxy or (2) R₁ is hydroxy and R₂ is amino are of particular use aschemical intermediates as described in more detail hereafter.

Also part of this invention are acid addition salts of the bases ofFormula I with pharmaceutically acceptable organic and inorganic acidssuch as those with hydrochloric, hydrobromic, hydriodic, sulfuric,methanesulfonic, tartaric, maleic, fumaric, succinic, ethanedisulfonicor phosphoric acids.

The acid addition salts are prepared by reacting the bases in an organicsolvent such as methanol or ethanol with an excess of acid as well as byother methods known to the art. It will be recognized that when one ofR₁ or R₂ of the structures is a primary amine two mole equivalents ofacid are necessary.

It will also be obvious to one skilled in the art that the compounds ofFormula I may be present as diastereoisomers which may be resolved intod, 1 optical isomers. Resolution of the optical isomers may beconveniently accomplished by fractional crystallization of their saltswith optically active acids from appropriate solvents. Unless otherwisespecified herein or in the claims, it is intended to include allisomers, whether separated or mixtures thereof. Where isomers areseparated, the desired pharmacological activity will usually predominatein one of the isomers.

The compounds of Formula I are prepared by two chemical methods. Thefirst and most convenient is outlined in Sequence A. ##STR2##

In Sequence A, R and R₃ are as defined for Formula I, R₄ is allyl,methyl, or a nitrogen protecting group such as benzyl, R₅ representshydrogen or phenyl optionally substituted by one or more substituentscommon to the art and R₆ represents phenyl also optionally substituted.When the outlined reactions are used to prepare compounds of Formula Iin which R₄ is other than hydrogen such as methyl or allyl theN-protecting group is not needed.

In Sequence A, a7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine suitablyprotected at the 3- or N-position of the ring by a nitrogen protectinggroup known to the art (II) is treated with a mild oxidizing agent suchas silver oxide or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to form the7,8-quinone (III) such as in U.S. Pat. No. 4,108,989. The quinone istreated with a slight molar excess of a suitable primary amine such asbenzhydrylamine or benzylamine to give a mixture of 7,8-mono-imine orSchiff bases (IV). Most conveniently the oxidation and imine steps arecarried out without isolation of the quinone. The Schiff bases arehydrolyzed with dilute acid, usually alcoholic hydrogen chloride at roomtemperature. The resulting 7,8-hydroxy,amino-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine mixture is thenN-acylated using acetic anhydride in methanol followed by basehydrolysis of any acetate esters formed, and the resulting7,8-acetamido, hydroxy compound mixture is purified by fractionalcrystallization or chromatography to give the individual isomericcompounds of Formula I with structures in which R₁ and R₂ are hydroxyand acetamido optionally protected at position 3. When the protectivegroups are removed such as by catalytic hydrogenation in case of the3-benzyl or aqueous acid for N-acetyl moieties, the parent1-phenylbenzazepine amino-alcohols of this invention are recovered.##STR3##

R and R₃ are as defined for Formula I but, of course, R₃ shall not be areactive unprotected group such as hydroxy.

In the second general method of preparing the compounds of thisinvention illustrated in Sequence B,1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines with structures having a7- or 8-hydroxy substituent and with the 3- or N-hydrogen protected aremono-nitrated, for example, in glacial acetic acid with fuming nitricacid at ambient temperature to give the 7,8-nitro, hydroxy substitutedintermediates (VII). These are reduced, either as such or afterO-benzylation, by controlled catalytic hydrogenation using palladium orplatinum catalysts. The hydrogenation may be stopped at reduction of thenitro group or may be continued to remove the protective benzyl groups.The latter is most conveniently carried out using palladium-on-charcoalin alcoholic solution at ambient temperature and from 40-65 p.s.i.

Alternatively the 7,8-amino,hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine of Formula I can beprepared by reducing the 7,8-nitro, hydroxy congeners of Formula X usinglow pressure catalytic hydrogenation conditions with platinum oxide ascatalyst: ##STR4## in which R and R₃ are as described for Formula I.

The compounds of Formula X have weak biological activity such as acentral dopaminergic effect but are most useful as chemicalintermediates as disclosed hereafter.

The compounds of this invention having structures which include anN-acylated amino group at the 7 or 8 positions of the benzazepinenucleus are prepared most conveniently by the following route: ##STR5##

Also part of this invention are certain O- or N-benzylated intermediatesof the general formula: ##STR6## in which R and R₃ are as defined forFormula I, R₁ is amino, acetamido, nitro or methylsulfonamidoyl, R₂ isbenzyloxy or, when R₁ is nitro, hydroxy, and R₄ is benzyl, methyl, allylor, when R₁ is nitro, hydrogen. The compounds in which R₁ is amino arekey intermediates in the preparation of other pharmacologically activecompounds.

The new compounds of Formula I have pharmacodynamic activity on thecentral nervous and cardiovascular systems. More specifically they havebeen demonstrated to have activity in animal tests indicating sedative,antidepressant or dopaminergic activities. For example in the standardtest procedure reported by Ungerstedt et al., in Brain Research 24,1970, 485-493 which indicates central dopaminergic activity or morespecifically antiparkinsonism activity the following results wereobtained:

8-amino-7-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinedihydrochloride at 5.0 μg/rat intracaudally gave 1216±96 rotations at 2hours and at 10.0 mg/kg intraperitoneally gave 92±64 rotations at 2hours.7-Hydroxy-8-methanesulfonamido-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinefumarate at 1.0 μg/rat intracaudally but not intraperitoneally gave120±79 rotations at 2 hours.8-Acetamido-7-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride at 2 μg/rat intracaudally gave 57±27 rotations. None ofthese compounds demonstrated peripheral dopaminergic activity asmeasured in the renal vasodilator test procedure described in U.S. Pat.No. 4,165,372, at doses of up to 6 μg/kg/min.7-Hydroxy-8-nitro-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride gave 55±25 rotations at 10 mg/kg intraperitoneally andsignificant rotation intracaudally at 0.1, 1.0 and 5.0 μg/rat in thecentral dopaminergic test.

In the anesthetized dog procedure for peripheral dopaminergic activityof U.S. Pat. No. 4,165,372,7-amino-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinedihydrochloric had an ED₁₅ of 26 μg/kg and in the rotation test gave314±38 rotations at 10 mg/kg intraperitoneally.7-Acetamido-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine had aperipheral ED₁₅ of 420 μg/kg and 732 rotations at 0.1 μg/ratintracaudally in the central dopaminergic test.

7-Amino-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinedihydrochloride gave an ED₅₀ of 15.0 mg/kg intraperitoneally inpreventing the ptosis caused by 1.25 mg/kg of reserpine indicatingantidepressant activity equivalent to imipramine (8.35 mg/kg) at twicethe dose in this standard pharmacological procedure. This compound alsodemonstrated sedation at an intraperitoneal dose of 37.8 mg/kg in rats.Its N-methylsulfonyl derivative demonstrated sedation at 50 mg/kg. The7-amino compound gave significant diuretic activity in the standardphosphate-mannitol renal clearance method.

The pharmaceutical compositions containing a compound of Formula I whichhas biological activity are prepared in conventional dosage unit formsby incorporating the chemical compound or a pharmaceutically acceptableacid addition salt thereof, with a nontoxic pharmaceutical carrieraccording to accepted procedures in a nontoxic amount sufficient toproduce the desired pharmacodynamic activity in a subject, animal orhuman. Preferably the compositions will contain the active ingredient inan active but nontoxic amount selected from about 150 mg. to about 1000mg. of active ingredient per dosage unit but this quantity depends onthe specific biological activity desired and the conditions of patient.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier for oral administration is used the preparation can be tableted,placed in a hard gelatin capsule in powder or pellet form, or in theform of a suppository, trouche or lozenge. The amount of solid carrierwill vary widely but preferably will be from about 25 mg. to about 1 g.If a liquid carrier is used, the preparation will be in the form of asyrup, emulsion, soft gelatin capsule, sterile injectable liquid such asan ampul, or an aqueous or nonaqueous liquid suspension.

The pharmaceutical preparations are made following the conventionaltechniques of the pharmaceutical chemist involving mixing, granulatingand compressing when necessary, or variously mixing and dissolving theingredients as appropriate to give the desired end product.

The method of producing pharmacodynamic activity comprises administeringinternally to a subject in need of such activity a compound of Formula Ior a pharmaceutically acceptable acid addition salt thereof, usuallycombined with a pharmaceutical carrier, in a nontoxic amount sufficientto produce said activity as described above. The route of administrationmay be any route which effectively transports the active compound to thereceptor sites which are to be affected such as orally or parenterally.Advantageously, equal doses will be administered several times such astwo or three times a day with the daily dosage regimen being selectedfrom about 300 mg. to about 2 g.

The following examples are designed solely to illustrate the preparationand use of the compounds of this invention. The temperatures areCentigrade. The doses outlined herein are in terms of the base form ofthe compounds of Formula I. Other variations of these examples will beobvious to those skilled in the art.

EXAMPLE 1

A mixture of 45 g. (0.134 mole) of7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide,138 g. (1 mole) of anhydrous potassium carbonate powder, 1 g. ofascorbic acid and 600 ml. of acetone was stirred after flushing withargon while 16.1 ml. (23.2 g., 0.136 mole) of benzyl bromide was added.The mixture was raised to reflux temperature, then heated at reflux for40 minutes. The cooled mixture was filtered into excess dilutehydrochloric acid. The acid mixture was evaporated in vacuo. The residuewas diluted with water and ethyl acetate then neutralized with sodiumhydroxide solution adding a small quantity of ascorbic acid. Near theend point, phosphoric acid and sodium carbonate were added to buffer themixture. At pH of 8, the organic layer was separated. The aqueous layerwas extracted twice with ethyl acetate. The combined organic extractswere dried then concentrated to yield 52.9 g. of3-benzyl-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine asthe etherate after trituration under ether, m.p 90° (dec.).

A mixture of 16.7 g, (0.0395 mole) of the 3-benzyl compound, 36.6 g.(0.150 mole) of silver oxide, 8.7 g. (0.0475 mole) of benzhydryl amine,11.4 g. (0.08 mole) of sodium sulfate and 150 ml. of ethyl acetate wasstirred under argon at room temperature for 1.5 hours. Thin layeranalysis (70% benzene-30% ethyl acetate, Rf of benzyl compound=0.53)indicated reaction was complete. The reaction mixture was filtered. Thefiltrate was evaporated in vacuo. The residue therefrom was dissolved in150 ml. of methanol and treated with 50 ml. of 3N hydrochloric acid.After 1 hour at room temperature, hydrolysis of the imines was complete(Rf=0.38 same system).

Most of the methanol was evaporated in vacuo. The residue was dilutedwith 200 ml. of water with 0.5 g. of ascorbic acid. After adjusting thepH to 8 using 40% sodium hydroxide solution the mixture was bufferedusing dilute sodium carbonate and 1M phosphoric acid. The mixture wasextracted with ethyl acetate. The combined dried extract was evaporated.The residue which was a mixture of 7,8-amino, hydroxy position isomerswas dissolved in 200 ml. of methanol and 16.2 g. (0.16 mole) of aceticanhydride added in two portions 30 minutes apart. After standingovernight, an excess of 40% sodium hydroxide was added followed by briefheating on the steam bath. Most of the organic solvent was evaporated invacuo after acidification. The residue was diluted with water thenextracted with ethyl acetate with back extraction with dilute phosphoricacid. The combined aqueous phases were adjusted to pH 8-9 with sodiumhydroxide and again extracted with ethyl acetate. The dried organicextracts from the pH 8-9 aqueous phase were evaporated to give aresidue. The residue was dissolved in benzene and passed over a silicagel column with elution with ethyl acetate-benzene mixtures.Crystallization from ethyl acetate-hexane gave 2.01 g. (13%) of7-acetamido-3-benzyl-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine(m.p. 203°-205°, Rf=0.26) and 3.41 g. (22%) of8-acetamido-3-benzyl-7-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine(m.p. 178°-180°, Rf=0.42, benzene-ethylacetate).

A mixture of 0.50 g. (0.0013 mole) of the 8-acetamido-3-benzyl compoundin 50 ml. of methanol was acidified with hydrochloric acid andhydrogenated with 1.0 g. of 10% palladium on charcoal at 60 p.s.i. After3 hours, the mixture was flushed with argon, filtered and evaporated.The residue was taken up in 5% phosphoric acid and washed with ethylacetate. The acid solution was adjusted to pH 8-8.5 with 40% sodiumhydroxide then extracted with ethyl acetate. Drying and evaporating invacuo gave 365 mg. (95%) of white solid,8-acetamido-7-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine. Thehydrochloride hydrate was prepared using hydrogen chlorideetherealmethanol, m.p. 181.5°.

EXAMPLE 2

A mixture of 16.3 g. (0.0385 mole) of3-benzyl-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine and225 ml. of ethanol-methanol was treated with 10.7 g. (0.00462 mole) of2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in methanol-ethanol withcooling. After stirring for 30 minutes at 0°, the precipitate isfiltered, washed with ethyl acetate and then ether. The quinone isstirred with 200 ml. of tetrahydrofuran and 15 g. of 5A° molecularsieves while a mixture of 10.6 g. (0.0578 mole) of benzhydrylamine in 30ml. of tetrahydrofuran was added. The reaction mixture was used andworked up as in Example 1 to give 8.5 g. (57%) of 7,8-amino, hydroxyisomers. Separation of the isomers as described above but withrecrystallization from ether gave8-acetamido-3-benzyl-7-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine,m.p. 180.5°, and its 7,8-isomer, m.p. 205°-207°.

EXAMPLE 3

A mixture of 3.0 g. (0.078 mole) of8-acetamido-3-benzyl-7-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepineand 150 ml. of concentrated hydrochloric acid was heated at reflux for 2hours. The mixture was evaporated in vacuo then again with added tolueneto give 3.1 g. of yellow solid,8-amino-3-benzyl-7-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

The solid was dissolved in 100 ml. of aqueous ethanol and hydrogenatedwith 2 g. of 10% palladium-on-charcoal. After 2 hours, the mixture wasflushed, filtered and evaporated to a volume of 15 ml. Cooling overnightgave 1.8 g. (75%) of8-amino-7-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine,m.p. >320° as the dihydrochloride salt.

EXAMPLE 4

A mixture of 4.0 g. (0.010 mole) of7-acetamido-3-benzyl-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine,0.57 ml. (0.0097 mole) of glacial acetic acid and 150 ml. ofmethanol-ethyl acetate was hydrogenated over 4.0 g. of 10%palladium-on-charcoal at 60 p.s.i. After 1.5 hours, the mixture wasflushed with argon and filtered. The filtrate was evaporated in vacuo at45°-50° to give a yellow-green oily residue. The residue was dissolvedin water. The aqueous solution was neutralized with sodium carbonate togive 2.7 g. (87%) of white solid7-acetamido-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p.133°-143°.

EXAMPLE 5

A mixture of 3.0 g. (0.00776 mole) of7-acetamido-3-benzyl-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-2,3,4,5-tetrahydro-1H-3-benzazepine,0.44 g. (0.0078 mole) of acetic acid and 100 ml. of methanol-ethylacetate (9:1) was hydrogenated over 2.0 g. of 10% palladium-on-charcoal.After working up as described in Example 4, 1.8 g. (78%) of7-amino-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinedihydrochloride, m.p. 231°-235°, was isolated.

EXAMPLE 6

A mixture of 72.0 g. (0.301 mole) of8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine, 51.5 g. (35.8ml, 0.301 mole) of α-bromotoluene and 45.0 g. (0.325 mole) of potassiumcarbonate in 1 l. of acetone was stirred at room temperature for 4hours. The reaction mixture was filtered and the filtrate was evaporatedto dryness in vacuo. The residue was treated with water and extractedwith ether. The ether extracts were dried, treated with charcoal andevaporated in vacuo. The residue was taken up in benzene, then filteredto remove some isoluble material and diluted with hexane to give, oncooling, 67.3 g. (67.9%) of an off-white crystalline, m.p.136.5°-139.5°,3-benzyl-8hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

To a mixture of 20.0 g. (0.0607 mole) of3-benzyl-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine and 500ml. of acetic acid was added, dropwise, 3.0 ml. (4.44 g., 0.0634 mole)of 90% yellow fuming nitric acid. After stirring for 2 hours at roomtemperature the mixture was poured into water, neutralized with ammoniaand extracted with methylene chloride. The organic extract was dried andevaporated in vacuo. The residue was chromatographed over silica gelwith 25% ethyl acetatechloroform to give 11.2 g. (49%) of3-benzyl-8-hydroxy-7-nitro-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride. This was dissolved in ethanol, acidified with etherealhydrogen chloride and diluted with ether to give the hydrochloride salt,m.p. 264°-265° (dec.), 11.7 g. (47%).

This3-benzyl-8-hydroxy-7-nitro-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride (7.7 g., 0.019 mole) was hydrogenated in 100 ml. ofmethanol over 2 g. of 10% palladium-on-charcoal over 2 hours. Thereaction mixture was flushed with argon, filtered. The filtrate wasacidified wth ethereal hydrogen chloride (Congo Red). Concentration ofthe filtrate to 50 ml. followed by dilution with ether and cooling gave3.8 g. (63%) of a tan crystalline solid, m.p. 227°-229° (dec.),7-amino-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinedihydrochloride.

EXAMPLE 7

Three milliliters (0.0634 mole) of 90% fuming nitric acid was addeddropwise to a solution of 20.0 g. (0.0607 mole) of3-benzyl-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine preparedas described for its isomer above, m.p. 136.5°-139.5°, in 500 ml. ofglacial acetic acid. After 2 hours, the mixture was poured on ice andneutralized with ammonia then extracted with methylene chloride. Thedried extract was evaporated to 500 ml. Chromatography over silica withethyl acetate-chloroform (1:4) gave 11.15 g. (49%) of oily3-benzyl-8-hydroxy-7-nitro-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

EXAMPLE 8

A mixture of 1.8 g. of3-benzyl-7-hydroxy-8-nitro-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride was converted to crude base which was dissolved in 50 ml.of benzene and added to a mixture of 0.75 g. of cyanogen bromide inbenzene at 50°-55°. After 35 hours a small amount of unreacted startingmaterial was detected. Additional cyanogen bromide (0.2 g) was addedthen heat at 55° overnight was applied. The mixture was stripped. Amixture of 25 ml. of acetic acid and 40 ml. of 3N hydrochloric acid wasadded to the residue. The mixture was heated at reflux with stirringovernight. After filtering hot, the filtrate was evaporated in vacuo toa yellow solid. After recrystallization from methanol-ethyl acetate, 1g. (85%) of7-hydroxy-8-nitro-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloridewas recovered as the monohydrate.

Using the same reaction conditions and work up as above, 1.4 g. (0.0132mole) of cyanogen bromide in benzene (25 ml) and 4.12 g. (0.011 mole) of3-benzyl-8-hydroxy-7-nitro-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinewas reacted at 50°-55° to give8-hydroxy-7-nitro-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride, m.p. 252°-255° (dec.).

EXAMPLE 9

A mixture of 7.0 g. (0.0180 mole) of8-acetamido-3-benzyl-7-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine,2.3 g. (0.0180 mole) of benzyl chloride, 0.725 g. (0.0180 mole) of 40%sodium hydroxide and 450 ml. of aqueous acetic acid was heated at refluxovernight. The bulk of the acetone was evaporated in vacuo. The residuewas quenched with water then extracted with ethyl acetate. The extractswere washed with alkali, dried and evaporated to give 5.6 g. (65%) of8-acetamido-3-benzyl-7-benzyloxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine(Rf=0.53).

A mixture of 4.4 g. (0.0092 mole) of the dibenzyl compound and 110 ml.of 2% hydrochloric acid was heated at 95°-100° for several hours. Themixture was made basic with 10% sodium hydroxide then extracted withether. After drying, charcoaling and evaporating the extract gave, afteralumina chromatography, 2.5 g. (62.5%) of8-amino-3-benzyl-7-benzyloxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine,a key intermediate, m.p. 119°-120°.

EXAMPLE 10

A mixture of 6.2 g. (0.0143 mole) of the 8-amino compound from Example9, 1.72 g. (0.0150 mole) of methanesulfonyl chloride, 30 ml. oftriethylamine and 200 ml. of benzene was stirred at room temperatureovernight. Assay of the mixture indicated incomplete reaction. Anadditional 0.6 ml. (0.0075 mole) of sulfonyl chloride was added and thereaction continued until completion. The reaction mixture was washedwith alkali, dried and evaporated. The residual oil (8.1 g.) wasdissolved in methane and seeded to give crystalline3-benzyl-7-benzyloxy-8-methylsulfonamido-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine,m.p. 136°-138°.

This intermediate (3.55 g., 0.00693 mole) was dissolved inmethanol-ethanol (1:1) and hydrogenated over 10% palladium-on-charcoalin an acid medium. The mixture was flushed with argon, filtered and thefiltrate evaporated. The residue was taken up in water and neutralizedwith sodium carbonate. The resulting solid was taken up in methanol. Thefiltrate was reacted with an excess of fumaric acid in methanol. Afterfiltration ether is added to induce crystallization of 1.0 g. of7-hydroxy-8-methylsulfonamido-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehemifumarate hydrate, m.p. 178°-182° (dec.).

EXAMPLE 11

A mixture of 2 g. of3-benzyl-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide (prepared as described above from starting materialdisclosed in U.S. Pat. No. 4,108,989), 1.3 g. of sodium sulfate, 3.6 g.of silver oxide, 1.0 g. of benzylamine and 75 ml. of ethyl acetate isstirred in an inert atmosphere for several hours. Working up and furtherreaction as described above in Example 1 gives the 7,8-isomeric mixtureof benzylimino compounds of Formula IV in which R is chloro and R₃ ishydrogen, the two 7,8-acetamido,hydroxy-3-benzyl-6-chloro-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinesand finally, after hydrogenolysis,7-acetamido-6-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepineand8-acetamido-6-chloro-7-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

EXAMPLE 12

Repeating the reaction sequence and isolation procedures of Example 1but using

(a) 6-fluoro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine(U.S. Pat. No. 4,108,989),

(b) 6-propyl-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine(U.S. Pat. No. 4,165,372),

(c)7,8-dihydroxy-1-(3-trifluoromethylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine(U.S. Pat. No. 4,171,359),

(d)6-chloro-7,8-dihydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine(U.S. Pat. No. 4,171,359),

(e)6-chloro-7,8-dihydroxy-1-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine,

(f)6-chloro-7,8-dihydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine(U.S. Pat. No. 4,160,765) which does not require N-protection and

(g)3,6-dimethyl-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride (U.S. Pat. No. 4,165,372) which does not requireN-protection,

give compounds of this invention as follows:

(a)

8-acetamido-6-fluoro-7-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine

8-amino-6-fluoro-7-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine

7-acetamido-6-fluoro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepineand

7-amino-6-fluoro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine

(b)

8-acetamido-6-propyl-7-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine

8-amino-6-propyl-7-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine

7-acetamido-6-propyl-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepineand

7-amino-6-propyl-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine

(c)

8-acetamido-7-hydroxy-1-(3-trifluoromethylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepineand

7-acetamido-8-hydroxy-1-(3-trifluoromethylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine

(d)

8-acetamido-6-chloro-7-hydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine

8-amino-6-chloro-7-hydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine

7-acetamido-6-chloro-8-hydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepineand

7-amino-6-chloro-8-hydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine

(e)

8-acetamido-6-chloro-7-hydroxy-1-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine

8-amino-6-chloro-7-hydroxy-1-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine

7-acetamido-6-chloro-8-hydroxy-1-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine

7-amino-6-chloro-8-hydroxy-1-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine,and, after reacting the two acetamido products with 48% hydrobromic acidas described in U.S. Pat. No. 4,171,359,

8-amino-6-chloro-7-hydroxy-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepineand its dihydrobromide salt

7-amino-6-chloro-8-hydroxy-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepineand its dihydrobromide salt, as well as after N-allylation of the 7 or8-acetamido compound followed by hydrobromic acid treatment usingmethods described in U.S. Pat. No. 4,171,359.

3-allyl-8-amino-6-chloro-7-hydroxy-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepineand its dihydrochloride salt or its 7,8 isomer

(f)

8-acetamido-6-chloro-7-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine

7-acetamido-6-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine

(g)

8-amino-3,6-dimethyl-7-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine

7-amino-3,6-dimethyl-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

These compounds are conveniently isolated as the base or one of itshydrohalide or methanesulfonate salts.

What is claimed is:
 1. The method of preparing a 7-hydroxy-8-acetamidoor a 7-acetamido-8-hydroxy compound of the formula: ##STR7## in which: Ris hydrogen, halo or lower alkyl of 1-3 carbons;R₃ is hydrogen, halo,methyl, methoxy, methylthio or hydroxy; and R₄ is methyl, allyl orbenzyl, comprising the steps of: A. reacting a compound of thestructure: ##STR8## in which R, R₃ and R₄ are as defined above, withbenzylamine or benzhydrylamine to form a mixture of 7- or 8-hydroxy,benzylimines or of 7- or 8-hydroxy, benzhydrylimines, respectively; B.reacting either said imine mixture with alcoholic hydrogen chloride toform the 7- or 8-hydroxy, amino compounds; C. reacting said 7- or8-hydroxy, amino compounds with acetic anhydride or acetyl chloride toform the 7- or 8-O-acetyl, acetamido compounds; D. reacting said 7- or8-O-acetyl, acetamido compounds with sodium hydroxide solution to formthe desired 7- or 8-hydroxy, acetamido compounds; and E. separating byfractional crystallization or chromatography and isolating said7-hydroxy-8-acetamido or 7-acetamido-8-hydroxy compounds as definedabove by known chemical methods.
 2. The method of claim 1 in which R ishalo, R₃ is methoxy and R₄ is benzyl.
 3. The method of claim 1 in whichbenzylamine is used as a reactant.